Thiazolopyrimidine compounds, its production and use

ABSTRACT

Compounds represented by general formula (I):and salts thereof, exhibiting excellent adenosine A3 receptor antagonism: wherein A is an optionally substituted benzene ring; B may be further substituted; and R1 is an optionally substituted cyclic group.

TECHNICAL FIELD

The present invention relates to novel thiazolopyrimidine compoundshaving excellent adenosine A₃ receptor antagonistic activity, theirproduction, pharmaceutical compositions comprising them, and the like.

BACKGROUND ART

As subtypes of adenosine receptors, A₁, A_(2a), A_(2b) and A₃ are known.Adenosine induces bronchial constriction in asthma patients, whiletheophylline, which is known as an antiasthmatic, antagonizes adenosine.Recently several reports showed that activation of adenosine A₃receptors in rats promotes degranulation of mast cells [Journal ofBiological Chemistry, 268, 16887-16890 (1993)], that adenosine A₃receptors exist on peripheral blood eosinophils and that the stimulationof adenosine A₃ receptors activates phospholipase C and elevatesintracellular calcium concentration [Blood, 88, 3569-3574 (1996)].

Currently, as selective adenosine A₃ receptor antagonists, xanthinederivatives are reported in GB-A-2288733 and WO 95/11681, and thefollowing compounds are reported in Journal of Medicinal Chemistry, 40,2596-2608(1997).

WO 97/33879 discloses an adenosine A₃ receptor antagonist comprising acompound of the formula:

wherein R is hydrogen, chlorine, bromine, fluorine, iodine, hydroxy,C₁₋₄ alkyl, C₁₋₄ alkoxy or C₁₋₄ alkylcarboxy, or a salt thereof and,specifically discloses

On the other hand, as for thiazolopyrimidine compounds, the followingcompounds are reported.

1) As a compound having immunostimulating activity, a compoundrepresented by the formula:

wherein X is nitrogen atom or R₂—C group, R is hydrogen atom, apharmaceutically acceptable cation or alkyl group (C₁₋₅), R₁ and R₂ arethe same and different and are hydrogen atom, alkyl group (C₁₋₅) or,aralkyl, phenyl, thienyl or pyridyl group optionally substituted withhalogen atom, alkyl or alkoxy (the number of carbon atom of alkyl beingup to 4) or cycloalkyl group (C₁₋₅), or a pharmaceutically acceptablesalt, and specifically, the following compounds.

(JP 52-148096 A)

2) As a compound having anti-inflammatory activity, a compoundrepresented by the formula:

wherein (a) R^(a) together with R^(b) forms —C(R³)═CH—CO—N═ or (b) R^(a)is hydrogen atom and R^(b) is ═N—CO—CH═CH—NR⁷R⁸, R¹, R² and R³ are thesame or different, and are hydrogen atom, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₇carbonylalkoxy or phenyl, or R³ is as defined above and R¹ together withR² forms phenyl optionally substituted with two C₁₋₆ alkyls, C₁₋₆alkoxys, C₂₋₇ carbonylalkoxys, and R⁷ and R⁸ are independently hydrogenatom or C₁₋₆ alkyl, or they together with the adjacent nitrogen atomform pyrrolidino, piperidino or homopiperidino, and, the followingspecific compound:

(GB 1345148)

3) As agrochemicals,

(Journal of Agricultural and Food Chemistry, 39 (12), 2300-2303 (1991))

4)

(Journal für Praktische Chemie, 330 (4) 607-616 (1991))

5)

(Indian Journal of Chemistry, Section B, 23 B (2), 117-120 (1984))

6)

(Heterocyclics, 20 (6), 1089-1097 (1983))

7) As a compound having anti-microbial activity,

(Journal of Pharmaceutical Sciences, 62 (11), 1785-1789 (1973))

It is thought that adenosine causes asthma through its binding to anadenosine A₃ receptor, therefore A₃ adenosine receptor antagonists areexpected to become a new type of anti-asthma drug and the like.Accordingly, an agent for antagonizing adenosine at adenosine A₃receptors which has potent antagonistic activity, good oral absorptionand good metabolical stability are expected to have potent therapeuticeffects for asthma, inflammation, Addison's diseases, autoimmunehemolytic anemia, Crohn's diseases, psoriasis, rheumatism, central nervediseases (e.g., cerebrovacular disorders such as haemorrhagia cerebri,cerebral infarction, etc., head injury, spinal injury, cerebral edema,etc.), diabetes and the like. However, as a prophylactic and therapeuticagent for adenosine A₃ receptor-related diseases, no good agent forantagonising adenosine at adenosine A₃ receptors are known in terms ofpotency, safety, bioavailability, metabolic stability, and the like.Therefore, a good agent for antagonising adenosine at adenosine A₃receptors is expected to be developed.

DISCLOSURE OF THE INVENTION

As a result of the present inventors' intensive study, a compoundrepresented by the formula (I):

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and R¹ is an optionally substituted cyclicgroup, or a salt thereof [hereinafter sometimes abbreviated to compound(I)], whose chemical structure is characterized in that the 2-positionof the thiazolopyrimidine ring is substituted with an optionallysubstituted cyclic group and the 3-position thereof is substituted withan optionally substituted benzene ring, has been synthesized for thefirst time, and it has been found that the resultant compound (I) has anunexpected, excellent selective affinity to adenosine A₃ receptor andantagonistic activity at an adenosine A₃ receptor and high stabilitysuitable for a medicine, due to its specific chemical structure, and itis therefore satisfactory as a medicine. Further, the present inventorshave also found that a compound represented by the formula (Ia):

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and ring D may further be substituted, providedthat the, when the 5-position of the thiazolopyrimidine ring (ring B) issubstituted by amino, the 2 position thereof (ring D) is substituted, ora salt thereof [hereinafter sometimes abbreviated to compound (Ia)]including compound (I) has an unexpected, excellent selective affinityto adenosine A₃ receptor and antagonistic activity at an adenosine A₃receptor. On the basis of these findings, the inventors have completedthe present invention.

That is, the present invention relates to:

1. A compound represented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B may befurther substituted, and R¹ is an optionally substituted cyclic group,or a salt thereof;

2. The compound according to the above 1, wherein ring A is benzene ringwhich may have 1 to 5 substituents selected from the group consisting of(i) halogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro, (iv) cyano, (v)optionally halogenated C₁₋₆ alkyl, (vi) optionally halogenated C₂₋₆alkenyl, (vii) carboxy C₁₋₆ alkyl, (viii) carboxy C₂₋₆ alkenyl, (ix)optionally halogenated C₂₋₆ alkynyl, (x) optionally halogenated C₃₋₆cycloalkyl, (xi) C₆₋₁₄ aryl, (xii) optionally halogenated C₁₋₆ alkoxy,(xiii) C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, (xiv) hydroxy, (xv) C₆₋₁₄aryloxy, (xvi) C₇₋₁₆ aralkyloxy, (xvii) mercapto, (xviii) optionallyhalogenated C₁₋₆ alkylthio, (xix) C₆₋₁₄ arylthio, (xx) C₇₋₁₆aralkylthio, (xxi) amino, (xxii) mono-C₁₋₆ alkylamino, (xxiii)mono-C₆₋₁₄ arylamino, (xxiv) mono-C₇₋₁₆ aralkylamino, (xxv) di-C₇₋₁₆aralkylamino, (xxvi) di-C₁₋₆ alkylamino, (xxvii) di-C₆₋₁₄ arylamino,(xxviii) formyl, (xxix) carboxy, (xxx) C₁₋₆ alkyl-carbonyl, (xxxi) C₃₋₆cycloalkyl-carbonyl, (xxxii) C₁₋₆ alkoxy-carbonyl, (xxxiii) C₆₋₁₄aryl-carbonyl, (xxxiv) C₇₋₁₆ aralkyl-carbonyl, (xxxv) C₆₋₁₄aryloxy-carbonyl, (xxxvi) C₇₋₁₆ aralkyloxy-carbonyl, (xxxvii) 5- or6-membered heterocyclic-carbonyl which contains, in addition to carbonatoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, (xxxviii) carbamoyl, (xxxix) thiocarbamoyl, (xxxx)mono-C₁₋₆ alkyl-carbamoyl, (xxxxi) di-C₁₋₆ alkyl-carbamoyl, (xxxxii)C₆₋₁₄ aryl-carbamoyl, (xxxxiii) 5- or 6-membered heterocyclic-carbamoylwhich contains, in addition to carbon atoms, 1 to 3 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, (xxxxiv) C₁₋₆alkylsulfonyl, (xxxxv) C₆₋₁₄ arylsulfonyl, (xxxxvi) formylamino,(xxxxvii) C₁₋₆ alkyl-carbonylamino, (xxxxviii) C₆₋₁₄ aryl-carbonylamino,(xxxxix) C₁₋₆ alkoxy-carbonylamino, (xxxxx) C₁₋₆ alkylsulfonylamino,(xxxxxi) C₆₋₁₄ arylsulfonylamino, (xxxxxii) C₁₋₆ alkyl-carbonyloxy,(xxxxxiii) C₆₋₁₄ aryl-carbonyloxy, (xxxxxiv) C₁₋₆ alkoxy-carbonyloxy,(xxxxxv) mono-C₁₋₆ alkyl-carbamoyloxy, (xxxxxvi) di-C₁₋₆alkyl-carbamoyloxy, (xxxxxvii) C₆₋₁₄ aryl-carbamoyloxy, (xxxxxviii)nicotinoyloxy, (xxxxxix) 5- to 7-membered saturated cyclic amino whichmay be substituted by a substituent selected from the group consistingof C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-memberedaromatic heterocyclic group which contains, in addition to carbon atoms,1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom, and oxo, (xxxxxx) 5- to 10-membered aromatic heterocyclic groupwhich contains, in addition to carbon atoms, 1 to 4 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, and (xxxxxxi)sulfo (hereinafter referred to as C group-substituents), ring B mayfurther have 1 or 2 substituents selected from the C group substituents,and R¹ is C₃₋₆ cycloalkyl group, C₁₋₁₄ aryl group or a monovalent groupformed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring which contains, in addition to carbon atom(s), 1 to 4hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,each of which may have 1 to 5 substituents selected from the C groupsubstituents;

3. The compound according to the above 2, wherein R¹ is a monovalentgroup formed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring which contains, in addition to carbon atom(s), 1 to 4hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom,and which may have 1 to 5 substituents selected from the C groupsubstituents as defined in the above 2;

4. The compound according to the above 2 or 3, wherein the 5- to14-membered heterocyclic ring is (i) 5- to 14-membered aromaticheterocyclic ring selected from the group consisting of thiophene,benzo[b]thiophene, benzo[b]furan, benzimidazole, benzoxazole,benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, pyrrole,imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole,isoindole, 1H-indazole, purine, 4H-quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole,isothiazole, phenothiazine, isoxazole, furazan and phenoxazine, or aring formed by this ring fused to one or two benzene rings, (ii) 5- to10-membered aliphatic heterocyclic ring selected from the groupconsisting of pyrrolidine, imidazoline, pyrazolidine, pyrazoline,piperidine, piperazine, morpholine, thiomorpholine, dioxazole,oxadiazoline, thiadiazoline, triazoline, thiadiazole and dithiazole, or(iii) 7- to 10-membered bridged heterocyclic ring selected from thegroup consisting of quinuclidine and 7-azabicyclo[2.2.1]heptane;

5. The compound according to the above 2 or 3, wherein the monovalentgroup formed by removing any one hydrogen atom from the 5- to14-membered heterocyclic ring is 5- to 14-membered nitrogen-containingaromatic heterocyclic group which contains, in addition to carbonatom(s), 1 to 4 hetero atoms selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom;

6. The compound according to the above 2 or 3, wherein the monovalentgroup formed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group,8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group,4-isoquinolyl group, 5-isoquinolyl group, pyrazinyl group, 2-pyrimidinylgroup, 4-pyrimidinyl group, 3-pyrrolyl group, 2-imidazolyl group,3-pyridazinyl group, 3-isothiazolyl group, 3-isoxazolyl group, 1-indolylgroup, 2-indolyl group, 3-indolyl group or 2-benzothiazolyl group;

7. The compound according to the above 2 or 3, wherein the monovalentgroup formed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring is 5- or 6-membered nitrogen-containing aromaticheterocyclic group which contains, in addition to carbon atoms, 1 to 3hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom;

8. The compound according to the above 2 or 3, wherein the monovalentgroup formed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring is 2-pyridyl group, 3-pyridyl group, 4-pyridyl group,pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 3-pyrrolylgroup, 3-pyridazinyl group, 3-isothiazolyl group or 3-isoxazolyl group.

9. The compound according to the above 2 or 3, wherein the monovalentgroup formed by removing any one hydrogen atom from 5- to 14-memberedheterocyclic ring is pyridyl group;

10. The compound according to the above 1, wherein R¹ is 4-pyridylgroup;

11. The compound according to the above 1, wherein R¹ is an optionallysubstituted nitrogen-containing aromatic heterocyclic group;

12. The compound according to the above 1, wherein ring A is benzenering which may be substituted with C₁₋₆ alkoxy, or one or two C₁₋₆alkyls;

13. The compound according to the above 1, wherein ring A is benzenering which may be substituted with C₁₋₆ alkoxy;

14. The compound according to the above 1, wherein the substituent bywhich ring B may further be substituted is amino;

15. The compound according to the above 1, wherein ring A is benzenering which may be substituted with C₁₋₆ alkoxy, or one or two C₁₋₆alkyls, ring B may further be substituted with amino and R¹ is pyridylgroup;

16. The compound according to the above 1, wherein ring A is benzenering which may be substituted with C₁₋₆ alkoxy, ring B may further besubstituted with amino and R¹ is pyridyl group;

17. The compound according to the above 1 which is represented by theformula:

wherein R² and R³ are the same or different, and are hydrogen atom or asubstituent selected from the C group substituents, and ring A and R¹are as defined in the above 1, or a salt thereof;

18. The compound according to the above 17, wherein R³ is hydrogen atom;

19. (1)5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor its salt, (2)5-amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor its salt, or (3)5-amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor its salt;

20. A prodrug of the compound according to the above 1;

21. A process for producing the compound according to the above 1 or asalt thereof which comprises reacting a compound represented by theformula:

wherein each symbol is as defined above 1, or its salt, with a compoundrepresented by the formula:

R²—C≡C—COOH

wherein R² is as defined in the above 1, or its salt or reactivederivative, or a compound represented by the formula:

NCCHR³COOH

wherein R³ is as defined in the above 1, or its salt or reactivederivative;

22. A pharmaceutical composition comprising a compound represented bythe formula:

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and R¹ is an optionally substituted cyclicgroup, or a salt or a prodrug thereof;

23. The composition according to the above 22 which is an adenosine A₃receptor antagonist;

24. The composition according to the above 22 which is an agent forpreventing and/or treating diseases related to adenosine A₃ receptors;

25. The composition according to the above 22 which is an agent forpreventing and/or treating asthma or allergic disease;

26. The composition according to the above 22 which is an agent forpreventing and/or treating cerebrovascular disorders;

27. The composition according to the above 22 which is an agent forpreventing and/or treating head injury;

28. The composition according to the above 22 which is an agent forpreventing and/or treating cerebral edema;

29. An adenosine A₃ receptor antagonist comprising a compoundrepresented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and ring D may further be substituted, providedthat, when the 5-position of thiazolopyrimidine ring is substituted withamino, the 2-position thereof is substituted, or a salt thereof;

30. The antagonist according to the above 29, wherein ring A is benzenering which may have 1 to 5 substituents selected from the groupconsisting of (i) halogen atom, (ii) C₁₋₃ alkylenedioxy, (iii) nitro,(iv) cyano, (v) optionally halogenated C₁₋₆ alkyl, (vi) optionallyhalogenated C₂₋₆ alkenyl, (vii) carboxy C₁₋₆ alkyl, (viii) carboxy C₂₋₆alkenyl, (ix) optionally halogenated C₂₋₆ alkynyl, (x) optionallyhalogenated C₃₋₆ cycloalkyl, (xi) C₆₋₁₄ aryl, (xii) optionallyhalogenated C₁₋₆ alkoxy, (xiii) C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy, (xiv)hydroxy, (xv) C₆₋₁₄ aryloxy, (xvi) C₇₋₁₆ aralkyloxy, (xvii) mercapto,(xviii) optionally halogenated C₁₋₆ alkylthio, (xix) C₆₋₁₄ arylthio,(xx) C₇₋₁₆ aralkylthio, (xxi) amino, (xxii) mono-C₁₋₆ alkylamino,(xxiii) mono-C₆₋₁₄ arylamino, (xxiv) mono-C₇₋₁₆ aralkylamino, (xxv)di-C₇₋₁₆ aralkylamino, (xxvi) di-C₁₋₆ alkylamino, (xxvii) di-C₆₋₁₄arylamino, (xxviii) formyl, (xxix) carboxy, (xxx) C₁₋₆ alkyl-carbonyl,(xxxi) C₃₋₆ cycloalkyl-carbonyl, (xxxii) C₁₋₆ alkoxy-carbonyl, (xxxiii)C₆₋₁₄ aryl-carbonyl, (xxxiv) C₇₋₁₆ aralkyl-carbonyl, (xxxv) C₆₋₁₄aryloxy-carbonyl, (xxxvi) C₇₋₁₆ aralkyloxy-carbonyl, (xxxvii) 5- or6-membered heterocyclic-carbonyl which contains, in addition to carbonatoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom andsulfur atom, (xxxviii) carbamoyl, (xxxix) thiocarbamoyl, (xxxx)mono-C₁₋₆ alkyl-carbamoyl, (xxxxi) di-C₁₋₆ alkyl-carbamoyl, (xxxxii)C₆₋₁₄ aryl-carbamoyl, (xxxxiii) 5- or 6-membered heterocyclic-carbamoylwhich contains, in addition to carbon atoms, 1 to 3 hetero atomsselected from nitrogen atom, oxygen atom and sulfur atom, (xxxxiv) C₁₋₆alkylsulfonyl, (xxxxv) C₆₋₁₄ arylsulfonyl, (xxxxvi) formylamino,(xxxxvii) C₁₋₆ alkyl-carbonylamino, (xxxxviii) C₆₋₁₄ aryl-carbonylamino,(xxxxix) C₁₋₆ alkoxy-carbonylamino, (xxxxx) C₁₋₆ alkylsulfonylamino,(xxxxxi) C₆₋₁₄ arylsulfonylamino, (xxxxxii) C₁₋₆ alkyl-carbonyloxy,(xxxxxiii) C₆₋₁₄ aryl-carbonyloxy, (xxxxxiv) C₁₋₆ alkoxy-carbonyloxy,(xxxxxv) mono-C₁₋₆ alkyl-carbamoyloxy, (xxxxxvi) di-C₁₋₆alkyl-carbamoyloxy, (xxxxxvii) C₆₋₁₄ aryl-carbamoyloxy, (xxxxxviii)nicotinoyloxy, (xxxxxix) 5- to 7-membered saturated cyclic amino whichmay be substituted by a substituent selected from the group consistingof C₁₋₆ alkyl, C₆₋₁₄ aryl, C₁₋₆ alkyl-carbonyl, 5- to 10-memberedaromatic heterocyclic group which contains, in addition to carbon atoms,1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom, and oxo, (xxxxxx) 5- to 10-membered aromatic heterocyclic groupwhich contains, in addition to one nitrogen atom and carbon atoms, 1 to4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,and (xxxxxxi) sulfo (hereinafter referred to as C group substituents),

ring B may further have 1 or 2 substituents selected from the C groupsubstituents, and

ring D may further have a substituent selected from the C groupsubstituents;

31. A method for antagonizing adenosine A₃ receptors which comprisesadministrating to a mammal an effective amount of a compound representedby the formula:

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and ring D may further be substituted, providedthat, when the 5-position of thiazolopyrimidine ring is substituted withamino, the 2-position thereof is substituted, or its salt or itsprodrug;

32. A method for preventing and/or treating asthma, allergic disease,cerebrovascular disorders, head injury or cerebral edema which comprisesadministrating to a mammal an effective amount of a compound representedby the formula:

wherein ring A is an optionally substituted benzene ring, is ring B mayfurther be substituted, and R¹ is an optionally substituted cyclicgroup, or its salt or its prodrug;

33. Use of a compound represented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and ring D may further be substituted, providedthat, when the 5-position of thiazolopyrimidine ring is substituted withamino, the 2-position thereof is substituted, or its salt or itsprodrug, for manufacturing an adenosine A₃ receptor antagonist; and

34. Use of a compound represented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B mayfurther be substituted, and R¹ is an optionally substituted cyclic ring,or its salt or its prodrug, for manufacturing an agent for preventingand/or treating asthma, allergic disease, cerebrovascular disorders,head injury or cerebral edema.

Further, the present invention relates to:

35. A compound represented by the formula:

wherein R³ is a substituent, ring A is an optionally substituted benzenering, and R¹ is an optionally substituted cyclic group, or a saltthereof; and

36. An adenosine A₃ receptor antagonist comprising a compoundrepresented by the formula:

wherein R³ is a substituent, ring A is an optionally substituted benzenering, and ring D may further be substituted, or a salt thereof.

BEST EMBODIMENT OF THE INVENTION

In the above formulas, ring A is an optionally substituted benzene ring.

Examples of the optional “substituent” of ring A include halogen atom(e.g., fluorine, chlorine, bromine, iodine, etc.), C₁₋₃ alkylenedioxy(e.g., methylenedioxy, ethylenedioxy, etc.) nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, carboxyC₁₋₆ alkyl (e.g., carboxymethyl, carboxyethyl, etc.), carboxy C₂₋₆alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.),optionally halogenated C₂₋₆ alkynyl, optionally halogenated C₃₋₆cycloalkyl, C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), optionallyhalogenated C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g.,ethoxycarbonylmethyloxy, etc.), hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy,1-naphthyloxy, 2-naphthyloxy, etc.), C₇₋₁₆ aralkyloxy (e.g., benzyloxy,phenethyloxy, etc.), mercapto, optionally halogenated C₁₋₆ alkylthio,C₆₋₁₄ arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.),C₇₋₁₆ aralkylthio (e.g., benzylthio, phenethylthio, etc.), amino,mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino, etc.), mono-C₆₋₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.),mono-C₇₋₁₆ aralkylamino (e.g., benzylamino, phenethylamino, etc.),di-C₇₋₁₆ aralkylamino (e.g., dibenzylamino, diphenethylamino, etc.),di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino,etc.), di-C₆₋₁₄ arylamino (e.g., diphenylamino, etc.), formyl, carboxy,C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C₃₋₆cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, etc.), C₁₋₆ alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C₆₋₁₄aryl-carbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C₇₋₁₆aralkyl-carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), C₆₋₁₄aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), C₇₋₁₆aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl,etc.), 5- or 6-membered heterocyclic-carbonyl which contains, inaddition to carbon atoms, 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom (e.g., nicotinoyl, isonicotinoyl,thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), carbamoyl,thiocarbamoyl, mono-C₁₋₆ alkyl-carbamoyl (e.g., methylcarbamoyl,ethylcarbamoyl, etc.), di-C₁₋₆ alkyl-carbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C₆₋₁₄ aryl-carbamoyl(e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.),5- or 6-membered heterocyclic-carbamoyl which contains, in addition tocarbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygenatom and sulfur atom (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl,4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C₁₋₆alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C₆₋₁₄arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl,2-naphthylsulfonyl, etc.), formylamino, C₁₋₆ alkyl-carbonylamino (e.g.,acetylamino, etc.), C₆₋₁₄ aryl-carbonylamino (e.g., benzoylamino,naphthoylamino, etc.), C₁₋₆ alkoxy-carbonylamino (e.g.,methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino, etc.), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino, etc.), C₆₋₁₄ arylsulfonylamino(e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino, etc.), C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy, etc.), C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy,naphthylcarbonyloxy, etc.), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy, etc.), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ehtylcarbamoyloxy, etc.), di-C₁₋₆ alkyl-carbamoyloxy(dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy,etc.), nicotinoyloxy, 5- to 7-membered saturated cyclic amino which maybe substituted, 5- to 10-membered aromatic heterocyclic group whichcontains, in addition to carbon atoms, 1 to 4 hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom (e.g., 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl,5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl,2-benzo[b]thienyl, 3-benzo[b]thienyl, 2-benzo[b]furanyl,3-benzo[b]furanyl, etc.), sulfo and the like (hereinafter sometimesreferred to as C group substituents).

Ring A may have 1 to 5, preferably 1 to 3, more preferably 1 or 2substituents as mentioned above at possible positions thereof and, whenthe number of substituents is two or more, those substituents may be thesame as or different from one another.

The above-mentioned “optionally halogenated C₁₋₆ alkyl” includes, forexample, C₁₋₆ alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may have 1to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine, etc.). Specific examples thereof include methyl,chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl,3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.

The above-mentioned “optionally halogenated C₂₋₆ alkenyl” includes, forexample, C₂₋₆ alkenyl (e.g., vinyl, propenyl, isopropenyl, 2-buten-1-yl,4-penten-1-yl, 5-hexen-1-yl, etc.) which may have 1 to 5, preferably 1to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) andthe like.

The above-mentioned “optionally halogenated C₂₋₆ alkynyl” includes, forexample, C₂₋₆ alkynyl (e.g., 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl,etc.) which may have 1 to 5, preferably 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine, iodine, etc.), and the like.

The above-mentioned “optionally halogenated C₃₋₆ cycloalkyl” includes,for example, C₃₋₆ cycloalkyl (e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, etc.) which may have 1 to 5, preferably 1 to 3halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.).Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl,4-chlorocyclohexyl, etc.

The above-mentioned “optionally halogenated C₁₋₆ alkoxy” includes, forexample, C₁₋₆ alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) which may have1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine, etc.). Specific examples thereof include methoxy,difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy,propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,sec-butoxy, pentyloxy, hexyloxy, etc., and preferably methoxy, etc.

The above-mentioned “optionally halogenated C₁₋₆ alkylthio” includes,for example, C₁₋₆ alkylthio (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) which mayhave 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine,bromine, iodine, etc.). Specific examples thereof include methylthio,difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio,hexylthio, etc.

The above-mentioned “5- to 7-membered saturated cyclic amino” of the “5-to 7-membered saturated cyclic amino which may be substituted” includes,for example, 5- to 7-membered saturated cyclic amino optionallycontaining 1 to 4 hetero atoms of 1 or 2 species selected from the groupconsisting of nitrogen, sulfur and oxygen atoms in addition to carbonatoms and at least one nitrogen atom. Specific examples thereof includepyrrolidin-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino,tetrahydroazepin-1-yl, etc.

The “substituents” of the “5- to 7-membered saturated cyclic amino whichmay be substituted” include, for example, 1 to 3 substituents selectedfrom the group consisting of C₁₋₆ alkyl (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl,3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), C₁₋₆ alkyl-carbonyl (e.g.,acetyl, propionyl, etc.), and 5- to 10-membered aromatic heterocyclicgroup (e.g., 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl,2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, 3-benzo[b] furanyl, etc.), oxo,and the like.

Among the above substituents, optionally halogenated C₁₋₆ alkoxy and oneor two optionally halogenated C₁₋₆ alkyls are preferred. In particular,C₁₋₆ alkoxy and one to two C₁₋₆ alkyls are preferred, with two methyls,one tert-butyl, one methoxy, etc. being most preferred.

In the above formulas, ring B may further be substituted.

The optional “substituent(s)” of ring B are, for example, the same asthe optional substituent(s) of ring C (the C group substituents) and thelike.

As the optional “substituent(s)” of ring B, among others, preferred aregroups other than C₁₋₆ alkoxy-carbonyl, for example, halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), C₁₋₃ alkylenedioxy (e.g.,methylenedioxy, ethylenedioxy, etc.) nitro, cyano, optionallyhalogenated C₁₋₆ alkyl, optionally halogenated C₂₋₆ alkenyl, carboxyC₂₋₆ alkenyl (e.g., 2-carboxyethenyl, 2-carboxy-2-methylethenyl, etc.),optionally halogenated C₂₋₆ alkynyl, optionally halogenated C₃₋₆cycloalkyl, C₆₋₁₄ aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl,2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.), optionallyhalogenated C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl-C₁₋₆ alkoxy (e.g.,ethoxycarbonylmethyloxy, etc.), hydroxy, C₆₋₁₄ aryloxy (e.g., phenyloxy,1-naphthyloxy, 2-naphthyloxy, etc.), C₇₋₁₆ aralkyloxy (e.g., benzyloxy,phenethyloxy, etc.), mercapto, optionally halogenated C₁₋₆ alkylthio,C₆₋₁₄ arylthio (e.g., phenylthio, 1-naphthylthio, 2-naphthylthio, etc.),C₇₋₁₆ aralkylthio (e.g., benzylthio, phenethylthio, etc.), amino,mono-C₁₋₆ alkylamino (e.g., methylamino, ethylamino, etc.), mono-C₆₋₁₄arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.),di-C₁₋₆ alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino,etc.), di-C₆₋₁₄ arylamino (e.g., diphenylamino, etc.), mono-C₇₋₁₆aralkylamino (e.g., benzylamino, phenethylamino, etc.), di-C₇₋₁₆aralkylamino (e.g., dibenzylamino, diphenethylamino, etc.), formyl,carboxy, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, etc.), C₃₋₆cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, etc.), C₆₋₁₄ aryl-carbonyl (e.g., benzoyl,1-naphthoyl, 2-naphthoyl, etc.), C₇₋₁₆ aralkyl-carbonyl (e.g.,phenylacetyl, 3-phenylpropionyl, etc.), C₆₋₁₄ aryloxy-carbonyl (e.g.,phenoxycarbonyl, etc.), C₇₋₁₆ aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-memberedheterocyclic-carbonyl (e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl,morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl,pyrrolidin-1-ylcarbonyl, etc.), carbamoyl, thiocarbamoyl, mono-C₁₋₆alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C₁₋₆alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl, etc.), C₆₋₁₄ aryl-carbamoyl (e.g.,phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or6-membered heterocyclic-carbamoyl (e:g., 2-pyridylcarbamoyl,3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,3-thienylcarbamoyl, etc.), C₁₋₆ alkylsulfonyl (e.g., methylsulfonyl,ethylsulfonyl, etc.), C₆₋₁₄ arylsulfonyl (e.g., phenylsulfonyl,1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), formylamino, C₁₋₆alkyl-carbonylamino (e.g., acetylamino, etc.), C₆₋₁₄ aryl-carbonylamino(e.g., benzoylamino, naphthoylamino, etc.), C₁₋₆ alkoxy-carbonylamino(e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino,butoxycarbonylamino, etc.), C₁₋₆ alkylsulfonylamino (e.g.,methylsulfonylamino, ethylsulfonylamino, etc.), C₆₋₁₄ arylsulfonylamino(e.g., phenylsulfonylamino, 2-naphthylsulfonylamino,1-naphthylsulfonylamino, etc.), C₁₋₆ alkyl-carbonyloxy (e.g., acetoxy,propionyloxy, etc.), C₆₋₁₄ aryl-carbonyloxy (e.g., benzoyloxy,naphthylcarbonyloxy, etc.), C₁₋₆ alkoxy-carbonyloxy (e.g.,methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy,butoxycarbonyloxy, etc.), mono-C₁₋₆ alkyl-carbamoyloxy (e.g.,methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C₁₋₆ alkyl-carbamoyloxy(dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C₆₋₁₄aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy,etc.), nicotinoyloxy, 5- to 7-membered saturated cyclic amino which maybe substituted, 5- to 10-membered aromatic heterocyclic group (e.g.,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl,3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl,3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, 3-benzo[b]furanyl, etc.), sulfo and the like. Inparticular, amino and the like are preferred.

Ring B may have 1 or 2 substituents as mentioned above at possiblepositions thereof (5- or 6-position)), preferable one substituent at5-position, and, when the number of substituents is two or more, thosesubstituents may be the same as or different from one another.

In addition, the substituents at 5- and 6-position of ring B in thecompounds (I) and (Ia) can be indicated as R² and R³, respectively, asfollows.

R² and R³ may be any groups which can be present at 5-and 6-positions,respectively, and preferred examples include hydrogen atom and the like,in addition to the above-mentioned substituents of ring B. Inparticular, preferred R³ is hydrogen atom and, as R², amino group ispreferred.

In the above formulas, R¹ is a cyclic group which may be substituted.

The “cyclic group” of the “cyclic group which may be substituted”includes, for example, a cyclic hydrocarbon group, a heterocyclic groupand the like.

Examples of the above-mentioned “cyclic hydrocarbon group” includecycloalkyl group, aryl group and the like. Among them, a cyclichydrocarbon group having 1 to 16 carbon atoms is preferred.

As “cycloalkyl group”, for example, C₃₋₆ cycloalkyl group (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like arepreferred.

As “aryl group”, for example, C₆₋₁₄ aryl group (e.g., phenyl,1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl,2-anthryl, etc.) and the like are preferred.

As the above-mentioned “heterocyclic group”, there are, for example, amonovalent group formed by removing an optional hydrogen atom from a 5-to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic ringcontaining 1 to 4 hetero atoms of 1 or 2 species selected from the groupconsisting of nitrogen, sulfur and oxygen atoms in addition to carbonatoms, preferably, (i) a 5- to 14-membered, preferably, 5- to10-membered aromatic heterocyclic ring, (ii) a 5- to 10-memberedaliphatic heterocyclic ring and (iii) a 7- to 10-membered bridgedheterocyclic ring, etc.

The above-mentioned “5- to 14-membered (preferably 5- to 10-membered)aromatic heterocyclic ring” includes, for example, an aromaticheterocyclic ring such as thiophene, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isoxazole, furazan, phenoxazine, etc.; and a ring asformed through condensation of those rings (preferably a monocyclicring) with one or more (preferably one or two) aromatic rings (e.g.,benzene ring, etc.), etc.

The above-mentioned “5- to 10-membered aliphatic heterocyclic ring”includes, for example, pyrrolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, morpholine, thiomorpholine,dioxazole, oxadiazoline, oxathiazole, thiadiazoline, triazoline,thiadiazole, dithiazole, etc.

The above-mentioned “7- to 10-membered bridged heterocyclic ring”includes, for example, quinuclidine, 7-azabicyclo[2.2.1]heptane, etc.

Preferable examples of the “heterocyclic group” include, for example, a5- to 14-membered (preferably 5- to 10-membered) (monocyclic orbicyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2species selected from the group consisting of nitrogen, sulfur andoxygen atoms in addition to carbon atoms (e.g., 2-pyridyl, 3-pyridyl,4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl,3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, etc.).

When the heterocyclic group contains nitrogen atom (N) or sulfur atom(S), N or S may be oxidized (N-oxide, S-oxide).

Among these groups, a nitrogen-containing 5- or 6-membered aromaticheterocyclic group containing 1 to 3 hetero atoms selected from thegroup consisting of nitrogen, sulfur and oxygen atoms in addition tocarbon atoms (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl,2-pyrimidinyl, 4-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl,3-isoxazolyl, etc.) and the like are preferred. For example, pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl, in particular, 4-pyridyl, etc.)and the like are more preferred.

The “substituents” of the “cyclic group which may be substituted” arethe same as those mentioned above for the “substituents” of ring A.

The “cyclic group” may have 1 to 5, preferably 1 to 3 substituents asmentioned above at possible positions of the cyclic group and, when thenumber of substituents is two or more, those substituents may be thesame as or different from one another.

Further, for R¹, a basic group is preferred. As a basic group, pyridyl(e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), in particular, 4-pyridyl ispreferred.

In the above formula, ring D may further be substituted.

The further optional “substituent(s)” of ring D are the same as thosementioned above for the optional substituent(s) of ring A (C groupsubstituents). Preferably, the further optional substituent is the aboveR¹.

Preferred Example of Compound (Ia) is Compound (I).

Preferred example of compound (I) is that wherein R¹ is anitrogen-containing aromatic heterocyclic group which may be substitutedand ring B may have substituent(s) other than C₁₋₆ alkoxy-carbonyl.

More specifically, the followings are preferably used as compound (I):

(1) compound (I) wherein ring A is benzene ring which may be substitutedwith C₁₋₆ alkoxy or one or two C₁₋₆ alkyl, ring B may further have aminoand R¹ is pyridyl group, or a salt thereof;

(2) compound (I) wherein ring A is benzene ring which may be substitutedwith C₁₋₆ alkoxy, ring B may further have amino and R¹ is pyridyl group,or a salt thereof;

(3) 1)5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one,2)5-amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one,3)5-amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one,or a salt thereof;

(4)5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor a salt thereof.

Salts of compound (I) and compound (Ia) include, for example, metalsalts, ammonium salts, salts with organic bases, salts with inorganicacids, salts with organic acids, salts with basic or acidic amino acids,etc. Preferred examples of metal salts include alkali metal salts suchas sodium salts, potassium salts; alkaline earth metal salts such ascalcium salts, magnesium salts, barium salts; aluminum salts, etc.Preferred examples of salts with organic bases include salts withtrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine, etc. Preferred examplesof salts with inorganic acids include hydrochlorides, hydrobromides,nitrates, sulfates, phosphates, etc. Preferred examples of salts withorganic acids include formates, acetates, trifluoroacetates, phthalate,fumarates, oxalates, tartarates, maleates, citrates, succinates,malates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc.Preferred examples of salts with basic amino acids include salts witharginine, lysine, ornithine, etc. Preferred examples of salts withacidic amino acids include aspartates, glutamates, etc.

Among others, more preferred are pharmaceutically acceptable salts. Forexample, for the compound having an acidic functional group in themolecule, mentioned are their inorganic salts, such as alkali metalsalts (e.g., sodium salts, potassium salts, etc.), and alkaline earthmetal salts (e.g., calcium salts, magnesium salts, barium salts, etc.),ammonium salts, etc.; and for the compound having a basic functionalgroup in the molecule, mentioned are their salts with inorganic acidssuch as hydrobromides, nitrates, sulfates, phosphates, etc., and withorganic acids such as acetates, phthalates, oxalates, tartarates,maleates, citrate, succinates, methanesulfonates, p-toluenesulfonates,etc.

Processes for Producing Compound (I) are Mentioned Below.

Compound (I) can be produced by reacting a compound represented by theformula:

wherein each symbol is as defined above, or a salt thereof with acompound represented by the formula:

R²—C≡C—COOH

wherein R² is as defined above, or a salt thereof or a reactivederivative thereof, or a compound represented by the formula:

NCCHR³COOH

wherein R³ is as defined above, or a salt thereof or a reactivederivative thereof.

Examples of the reactive derivative to be used include a compound whosecarboxyl group is esterified with C₁₋₆ alkyl (e.g., methyl, ethyl,propyl, isopropyl, etc.), C₆₋₁₀ aryl (e.g., phenyl, naphthyl, etc.),etc., an acid halide such as an acid chloride, an acid anhydride, andthe like.

More specifically, compound (I) can be obtained by, for example, aprocess represented by the following Scheme 1 or its modification or,for example, modification of the process described in Journal ofHeterocyclic Chemistry, Vol. 25, pp. 949-953 (1988); ibid., Vol. 28, pp.489-492 (1991); JP 52-148096 A or GB 1345148; or the like.

In the following Scheme 1, R′ and R″ is hydrogen atom, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, etc.) or C₆₋₁₀ aryl (e.g., phenyl,naphthyl, etc.) and other symbols are as defined above. The compounds inthe Scheme also include those in the form of salts and examples of thesalts include the same salts as those exemplified with respect tocompound (I) and the like.

Scheme 1

Compound (II) can be obtained by a per se known process, for example,that described in JP 60-58981 A, JP 61-10580 A, JP 7-503023 A, WO93/15071, DE-A-3601411, JP 5-70446 A or the like, or its modification.

Compounds (III) and (IV) can be used commercial sources if they arecommercially available or can be produced in any per se known process.

Compound (I) is obtained by subjecting compound (II) to condensationwith an acetylenecarboxylic acid (III) or its reactive derivative, ifdesired, in the presence of an acid or a base.

The amount of compound (III) to be used is about 0.5 to about 3.0 mols,preferably about 0.8 to about 2.0 mols, relative to one mol of compound(II).

The amount of the acid or base to be used is about 1.0 to about 30 mols,preferably about 1.0 to about 10 mols, relative to one mol of compound(II).

The “acid” includes, for example, phosphoric acids such aspolyphosphoric acid, etc.; sulfonic acids such as methanesulfonic acid,p-toluenesulfonic acid, etc.; organic acids such as acetic acid, etc.;mineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, etc.; and the like.

The “base” includes, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, etc.; inorganic bases such assodium hydroxide, potassium hydroxide, etc.; aromatic amines such aspyridine, lutidine, etc.; tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydridessuch as sodium hydride, is potassium hydride, etc.; metal amides such assodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,etc.; metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide, etc.; and the like.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Examples of the solvent to be used include halogenated hydrocarbons,aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols,polyphosphoric acids, organic acids, water, and mixtures of two or moreof those solvents.

The reaction temperature is generally about −5 to about 200° C.,preferably about 5 to about 150° C. The reaction time is generally about5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

The product can be isolated from the reaction mixture in any ordinarymanner. This can be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

In addition, compound (I) is obtained by subjecting compound (II) tocondensation with a cyanoacetic acid (IV) or its reactive derivative, ifdesired, in the presence of an acid or a base.

The amount of compound (IV) to be used is about 0.5 to about 3.0 mols,preferably about 0.8 to about 2.0 mols, relative to one mol of compound(II).

The amount of the acid or base to be used is about 1.0 to about 30 mols,preferably about 1.0 to about 10 mols, relative to one mol of compound(II).

The “acid” includes, for example, phosphoric acids such aspolyphosphoric acid, etc.; organic acids such as acetic acid, etc.; andthe like.

The “base” includes, for example, basic salts such as sodium carbonate,potassium carbonate, cesium carbonate, etc.; inorganic bases such assodium hydroxide, potassium hydroxide, etc.; aromatic amines such aspyridine, lutidine, etc.; tertiary amines such as triethylamine,tripropylamine, tributylamine, cyclohexyldimethylamine,4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine,N-methylpyrrolidine, N-methylmorpholine, etc.; alkali metal hydridessuch as sodium hydride, potassium hydride, etc.; metal amides such assodium amide, lithium diisopropylamide, lithium hexamethyldisilazide,etc.; metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide, etc.; and the like.

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Examples of the solvent to be used include halogenated hydrocarbons,aliphatic hydrocarbons, aromatic hydrocarbons, ethers, amides, alcohols,polyphosphoric acids, organic acids, water, and mixtures of two or moreof those solvents.

The reaction temperature is generally about −5 to about 200° C.,preferably about 5 to about 150° C. The reaction time is generally about5 minutes to about 72 hours, preferably about 0.5 to about 30 hours.

The product can be isolated from the reaction mixture in any ordinarymanner. This can be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

Further, as shown by the following Scheme 2, compound (I) can beobtained from compound (V) and a metal cyanide compound (VI).

wherein L is a leaving group, M is a metal and other symbols are asdefined above.

Examples of the leaving group as L include halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.), C₁₋₅ alkylsulfonyloxy which may behalogenated (e.g., methanesulfonyloxy, ethanesulfonyloxy,trichloromethanesulfonyloxy, etc.), C₆₋₁₄ arylsulfonyloxy (e.g.,p-toluenesulfonyloxy, benzenesulfonyloxy, etc.), and the like.

Examples of the metal as M include sodium, potassium, copper, and thelike.

The compounds in the Scheme also include those in the form of salts andexamples of the salts include the same as those exemplified with respectto compound (I).

Compound (V) can be obtained by a per se known process, for example,that described in JP 60-58981 A, JP 61-10580 A, JP 7-503023 A, WO93/15071, DE-A-3601411, JP 5-70446 A or the like, or its modification.

Compound (VI) can be used commercial sources if they are commerciallyavailable or can be produced in any per se known process.

The amount of compound (VI) to be used is about 0.5 to about 5.0 mols,preferably about 0.8 to about 3.0 mols, relative to one mol of compound(IV).

This reaction is advantageously carried out in the absence of a solventor in an inert solvent. There is no particular limitation on the kind ofsolvent that can be used unless the reaction is interfered with.Examples of the solvent to be used include ethers, aromatichydrocarbons, aliphatic hydrocarbons, amides, halogenated hydrocarbons,nitrites, sulfoxides, ketones, aromatic amines, alcohols, water, andmixtures of two or more of those solvents.

The reaction temperature is generally about −5 to about 200° C.,preferably about 5 to about 50° C. The reaction time is generally about5 minutes to about 72 hours, preferably about 0.5 to about 15 hours.

The product can be isolated from the reaction mixture in any ordinarymanner. This can be easily purified through separation means such asrecrystallization, distillation, chromatography and the like.

In the above-mentioned reactions where the starting compounds aresubstituted by any of amino, carboxy or hydroxy, those groups may beprotected by ordinary protective groups which are generally used inpeptide chemistry. The protective groups may be removed after thereaction to give the desired products.

The amino-protecting group includes, for example, formyl, C₁₋₆alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may be substituted,phenylcarbonyl which may be substituted, C₁₋₆ alkoxy-carbonyl (e.g.,methoxycarbonyl, ethoxycarbonyl, etc.) which may be substituted,phenyloxycarbonyl which may be substituted, C₇₋₁₀ aralkyloxy-carbonyl(e.g., benzyloxycarbonyl, etc.) which may be substituted, trityl whichmay be substituted, phthaloyl which may be substituted, etc. Thesesubstituents include, for example, halogen atoms (e.g., fluorine,chlorine, bromine, iodine, etc.), C₁₋₆ alkyl-carbonyl (e.g., acetyl,propionyl, valeryl, etc.), nitro, etc. The number of those substituentsis 1 to 3.

The carboxy-protecting group includes, for example, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may besubstituted, phenyl which may be substituted, trityl which may besubstituted, silyl which may be substituted, etc. These substituentsincludes, for example, halogen atoms (e.g., fluorine, chlorine, bromine,iodine, etc.), formyl, C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl,butylcarbonyl, etc.), nitro, C₁₋₆ alkyl (e.g., methyl, ethyl,tert-butyl, etc.), C₆₋₁₀ aryl (e.g., phenyl, naphthyl, etc.), etc. Thenumber of those substituents is 1 to 3.

The hydroxy-protecting group includes, for example, C₁₋₆ alkyl (e.g.,methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.) which may besubstituted, phenyl which may be substituted, C₇₋₁₁ aralkyl (e.g.,benzyl, etc.) which may be substituted, formyl which may be substituted,C₁₋₆ alkyl-carbonyl (e.g., acetyl, propionyl, etc.) which may besubstituted, phenyloxycarbonyl which may be substituted, C₇₋₁₁aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, etc.) which may besubstituted, tetrahydropyranyl which may be substituted,tetrahydrofuranyl which may be substituted, silyl which may besubstituted, etc. Those substituents include, for example, halogen atoms(e.g., fluorine, chlorine, bromine, iodine, etc.), C₁₋₆ alkyl (e.g.,methyl, ethyl, tert-butyl, etc.), C₇₋₁₁ aralkyl (e.g., benzyl, etc.),C₆₋₁₀ aryl (e.g., phenyl, naphthyl, etc.), nitro, etc. The number ofthose substituents is 1 to 4.

Those protective groups may be removed by any per se known methods oranalogous methods thereto, such as treatment with acids, bases,ultraviolet rays, hydrazine, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate,etc.; and reduction, etc.

In any case, if desired, products formed in the reaction mixtures mayfurther be subjected to deprotection, acylation, alkylation,hydrogenation, oxidation, reduction, chain extension,substituents-exchange reaction and combined reactions thereof, to obtaincompound (I). These methods include, for example, the methods describedin “Shin Jikken Kagaku Kouza (New Edition of Lectures of ExperimentalChemistry)” 14, 15 (1977) edited by Maruzen.

The above “alcohols” include, for example, methanol, ethanol, propanol,isopropanol, tert-butanol, etc.

The above “ethers” include, for example, diethyl ether, diisopropylether, diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,etc.

The above “halogenated hydrocarbons” include, for example,dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride,etc.

The above “aliphatic hydrocarbons” include, for example, hexane,pentane, cyclohexane, etc.

The above “aromatic hydrocarbons” include, for example, benzene,toluene, xylene, chlorobenzene, etc.

The above “aromatic amines” include, for example, pyridine, lutidine,quinoline, etc.

The above “amides” include, for example, N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphoric triamide, etc.

The above “ketones” include, for example, acetone, methyl ethyl ketone,etc.

The above “sulfoxides” include, for example, dimethylsulfoxide, etc.

The above “nitriles” include, for example, acetonitrile, propionitrile,etc.

The above “organic acids” include, for example, acetic acid, propionicacid, trifluoroacetic acid, etc.

Where the products are formed in their free form in the above reaction,they may be converted into their salts in any ordinary manner. Wherethey are formed in the form of their salts, they may be converted intofree forms or other salts in any ordinary manner. The thus-obtainedcompound (I) may be isolated and purified from the reaction mixturesthrough any ordinary means of, for example, trans-salvation,concentration, solvent extraction, fractionation, crystallization,recrystallization, chromatography and the like.

Compound (Ia) other than compound (I) can be produced by the process forproducing compound (I) or a per se known process or their modifiedprocesses.

Where compounds (I) and (Ia) exist in the form of their configurationalisomers, diastereomers, conformers or the like, they may be optionallyisolated into single isomers through the separation and isolation meansmentioned above. Where compounds (I) and (Ia) are in the form of itsracemates, they may be separated into S— and R— forms through anyordinary optical resolution.

Where compounds (I) and (Ia) exist in the form of stereoisomers ortautomers, both single isomers and mixtures of different isomers areincluded within the scope of the present invention. For example, whencompound (I) have amino group at 5-position of the thiazolopyrimidinering, a compound represented by the formula:

wherein each symbol is as defined above, is included in the scope ofcompound (I) of the present invention.

Similarly, when compound (Ia) have amino group at 5-position of thethiazolopyrimidine ring, a compound represented by the formula:

where each symbol is as defined above, is included in the scope ofcompound (Ia) of the present invention.

Specifically, the followings are used as compound (I′) or compound(Ia′):

1)5-imino-3-(4-metoxyphenyl)-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one,2)5-imino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one,3)5-imino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-5,6-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-one,and the like.

Further, compounds (I) and (Ia) may be in any form of their hydrates andnon-hydrates.

Prodrugs of compounds (I) and (Ia) mean compounds that are convertedinto compounds (I) and (Ia) by a reaction with an enzyme, gastric acid,or the like under a physiological condition in a living body, namely,compounds that are converted into compounds (I) and (Ia) by an enzymaticoxidation, reduction, hydrolysis, or the like or compounds that areconverted into compound (I) and (Ia) by hydrolysis with gastric acid orthe like. Examples of the prodrug of compound (I) or (Ia) include acompound where the amino group in a compound (I) or (Ia) is acylated,alkylated, or phosphorylated (e.g., a compound where the amino group incompound (I) or (Ia) is converted into eicosanoylamino, alanylamino,pentylaminocarbonylamino,(5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino,tetrahydrofuranylamino, pyrrolidylmethylamino, pivaloyloxymethylamino,or tert-butylamino, etc.); a compound where the hydroxyl group incompound (I) or (Ia) is acylated, alkylated, phosphorylated, orconverted into the borate (e.g., a compound where the hydroxyl group incompound (I) or (Ia) is converted into acetyloxy, palmitoyloxy,propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, ordimethylaminomethylcarbonyloxy, etc.); a compound where the carboxylgroup in compound (I) or (Ia) is esterified or amidated (e.g., acompound where the carboxyl group in compound (I) or (Ia) is subjectedto ethyl esterification, phenyl esterification, carboxymethylesterification, dimethylaminomethyl esterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethyl esterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification,cyclohexyloxycarbonylethyl esterification, or conversion into the methylamide, etc.), and the like. These compounds can be produced fromcompounds (I) and (Ia) according to a well-known method.

Also, the prodrug of compounds (I) or (Ia) may be a compound that isconverted into compound (I) or (Ia) under a physiological condition asdescribed in “Iyakuhin No Kaihatu (Development of Drugs)”, Volume 7,Molecular Design, Hirokawa Shoten, published in 1990; page 163 to page198.

The agent of the present invention comprising compound (I) or (Ia) showsa high affinity for adenosine receptor, especially for adenosine A₃receptor, while having low toxicity and few side effects. The agent isuseful as a safe medicine.

The agent of the present invention comprising compound (I) or (Ia) has apotent adenosine A₃ receptor antagonistic activity on mammals (e.g.,mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human,etc.), a good oral absorption, a good metabolical stability, andtherefore, it can be used for preventing and/or treating diseases thatmay be related to adenosine A₃ receptor, for example, asthma, allergicdisease, inflammation, Addison's disease, autoimmune hemolytic anemia,Crohn's disease, psoriasis, rheumatism, central nerve diseases (e.g.,cerebrovacular disorders such as haemorrhagia cerebri, cerebralinfarction, etc., head injury, spinal injury, cerebral edema, etc.),diabetes, and so on. Preferred is an agent for prevention and/ortreatment of central nerve diseases, asthma, allergic disease, etc.

The agent of the present invention comprising compound (I) or (Ia) haslow toxicity, and therefore, compound (I) or (Ia) is, either directly asit is or after having been formulated into pharmaceutical compositionsalong with pharmaceutically acceptable carriers in any per se knownmanner, for example, into tablets (including sugar-coated tablets,film-coated tablets), powders, granules, capsules (including softcapsules), liquid preparations, injections, suppositories, sustainedrelease preparations, etc., safely administered orally or parenterally(e.g., locally, rectally, intravenously, etc.). In the pharmaceuticalcomposition of the present invention, the amount of compound (I) or (Ia)is from about 0.01 to about 100% by weight based on the total weight ofthe composition. The dose of the composition varies, depending on thesubject to which the composition is administered, the administrationroute employed, the disorder of the subject, etc. For example, as anadenosine A₃ receptor antagonist, oral composition for treating asthma,its dose for adults (body weight ca. 60 kg) may be from about 0.1 toabout 30 mg/kg of body weight, preferably from about 1 to about 20 mg/kgof body weight, in terms of the active ingredient (compound (I) or(Ia)), and this may be administered once or divided into several times aday.

Any ordinary organic and inorganic carrier substances that are generallyused in formulating medicines are usable as the carriers for formulatingthe pharmaceutical compositions of the present invention. For example,employable are ordinary excipients, lubricants, binders, disintegrators,etc. for formulating solid preparations; and solvents, solubilizers,suspending agents, isotonizing agents, buffers, soothing agents, etc.for formulating liquid preparations. If desired, further employable areother additives such as preservatives, antioxidants, colorants,sweeteners, adsorbents, wetting agents, etc.

The excipients include, for example, lactose, white sugar, D-mannitol,starch, corn starch, crystalline cellulose, light silicic anhydride,etc.

The lubricants include, for example, magnesium stearate, calciumstearate, talc, colloidal silica, etc.

The binders include, for example, crystalline cellulose, white sugar,D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethyl cellulose sodium, etc.

The disintegrators include, for example, starch, carboxymethylcellulose, carboxymethyl cellulose calcium, croscarmellose sodium,carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.

The solvents include, for example, water for injections, alcohol,propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc.

The solubilizers include, for example, polyethylene glycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane,cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc.

The suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecithin, benzalkonium chloride, benzethonium chloride, glycerinmonostearate, etc.; hydrophilic polymers such as polyvinyl alcohol,polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, etc.

The isotonizing agents include, for example, glucose, D-sorbitol, sodiumchloride, glycerin, D-mannitol, etc.

The buffers include, for example, liquid buffers of phosphates,acetates, carbonates, citrates, etc.

The soothing agents include, for example, benzyl alcohol, etc.

The preservatives include, for example, parahydroxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid, etc.

The antioxidants include, for example, sulfites, ascorbic acid,α-tocopherol, etc.

The present invention will be described in more detail hereinunder, withreference to the following Reference Examples, Examples, FormulationExamples and Experimental Examples, which, however, are to concretelyillustrate some embodiments of the invention and are not intended torestrict the scope of the invention. Various changes and modificationscan be made within the range that does not deviate the scope of theinvention.

“Room temperature” as referred to in the following Reference Examplesand Examples is meant to indicate a temperature falling between about10° C. and about 35° C. Unless otherwise specifically indicated, “%” isby weight. The yield indicates mol/mol %.

The meanings of the abbreviations used hereinunder are as follows:

s: singlet

d: doublet

br: broad

J: coupling constant

Hz: Hertz

CDCl₃: deuterated chloroform

¹H—NMR: proton nuclear magnetic resonance spectrum

DMSO: dimethylsulfoxide-d₆

REFERENCE EXAMPLE 1[4-(4-Methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine

2-Bromo-2-phenyl-1-(4-pyridyl)ethanone hydrobromide (11.0 g) wassuspended in a suspension of thiourea (2.22 g) in acetonitrile (170 mL),and triethylamine (4.1 mL) was slowly added dropwise thereto withstirring. After completion of the addition, the mixture was stirred atrefluxing temperature for 3 hours and then the solvent was distilledoff. Aqueous saturated sodium hydrogen carbonate solution was added tothe residue and the deposit was filtered off. The remaining mixture waswashed with water and ethyl ether and dried. The crude crystals obtainedwere recrystallized from pyridine to obtain the title compound (5.48 g,yield 68%).

m.p. 282-284° C.

REFERENCE EXAMPLE 2

(1) Reference Example Compound 2-1

[4-[4-(1,1-Dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 254-257° C. (ethanol).

(2) Reference Example Compound 2-2

[4-(3,5-Dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine

m.p. 242-244° C. (ethanol).

According to the same manner as that described in Reference Example 1,the above Reference Example Compounds 2-1 and 2-2 were synthesizedexcept that2-bromo-2-[4-(1,1-dimethylethyl)phenyl]-1-(4-pyridyl)ethanonehydrobromide and 2-bromo-2-(3,5-diemthylphenyl)-1-(4-pyridyl)ethanonehydrobromide were used, respectively, instead of2-bromo-2-(4-methoxyphenyl)-1-(4-pyridyl)ethanone hydrobromide.

REFERENCE EXAMPLE 3N-[4-[4-(1,1-Dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-chloroacetamideHydrochloride

Chloroacetyl chloride (0.55 g, 4.85 mmol) was added to a solution of[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine(1.0 g, 3.23 mmol) in N,N-dimethylacetaminde (10 mL) and the mixture wasstirred at 60° C. for 14 hours. The solvent was concentrated underreduced pressure and the resultant residue was washed with ether anddried. The crude crystals obtained was recrystallized from ethanol toobtain the title compound (0.94 g, yield 69%).

m.p. 267-269° C.

EXAMPLE 15-Amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one

To a suspension of[4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (1.0 g) inethanol were added in turn a 20% solution of sodium ethoxide in ethanol(1.4 mL) and ethyl cyanoacetate (0.40 g). The resultant mixture washeated under reflux for 8 hours. After distilling off the solvent, waterwas added to the residue, the mixture was neutralized with acetic acidand the precipitate formed was filtered off. The remaining crudecrystals were recrystallized from ethanol to obtain the title compound(0.52 g, yield 42%).

mp 267-271° C. ¹H-NMR (DMSO-d₆) δ: 3.78 (3H, s), 4.10 (2H, br s), 6.94(2H, d, J=8.8 Hz), 7.29 (2H, d, J=6.1 Hz), 7.37 (2H, d, J=8.8 Hz), 8.53(2H, d, J=6.1 Hz), 12.81 (1H, br s).

EXAMPLE 25-Amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one

To a solution ofN-[4-[4-(1,1-dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]-2-chloroacetamidehydrochloride (1.0 g) in dimethylsulfoxide (5 mL) was added sodiumcyanate (0.24 g). The mixture was stirred at room temperature for 14hours. An aqueous solution of sodium hydrogen carbonate was added to thereaction mixture and the mixture was extracted with a mixed solvent ofethyl acetate-tetrahydrofuran (1:1). The extract was washed with brine,dried over anhydrous sodium sulfate and filtered. The solvent wasconcentrated under reduced pressure and the residue was purified withsilica gel column chromatography (hexane-tetrahydrofuran, 1:1) andrecrystallized from ethyl acetate to obtain the title compound (0.14 g,yield 24%).

mp 259-262° C. ¹H-NMR (CDCl₃) δ: 1.36 (9H, s), 2.66 (2H, s), 7.25 (2H,d, J=5.9 Hz), 7.44 (2H, s), 8.57 (2H, d, J=5.9 Hz).

EXAMPLE 35-Amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-one

To a solution of[4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl)amine (1.0 g) inN,N-dimethylacetamide (10 mL) was added chloroacetyl chloride (0.60 g)and the mixture was stirred at 80° C. for 14 hours.N,N-Dimethylacetamide was distilled off under reduced pressure and theresultant residue was dissolved in dimethylsulfoxide (5 mL). To thissolution was added sodium cyanate (0.24 g) and the mixture was stirredat room temperature for 14 hours. An aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and the mixture wasextracted with a mixed solvent of ethyl acetate-tetrahydrofuran (1:1).The extract was washed with brine, dried over anhydrous sodium sulfateand filtered. The solvent was concentrated under reduced pressure andthe residue was purified by silica gel column chromatography(hexane-tetrahydrofuran, 1:1) and recrystallized from ethanol to obtainthe title compound (0.22 g, yield 18%).

mp 275-278° C. ¹H—NMR (CDCl₃) δ: 2.26 (6H, s), 3.73 (2H, s), 6.99 (1H,s), 7.06 (2H, s), 7.23 (2H, d, J=6.2 Hz), 8.50 (2H, d, J=6.2 Hz).

The chemical structural formulas of the compounds obtained in Examples 1to 3 are shown below.

EXAMPLE 1 COMPOUND

EXAMPLE 2 COMPOUND

EXAMPLE 3 COMPOUND FORMULATION EXAMPLE 1

(1) Example 1  50 mg (2) Lactose  34 mg (3) Corn starch 10.6 mg  (4)Corn starch (paste)  5 mg (5) Magnesium stearate  0.4 mg (6) Calciumcarboxymethyl cellulose  20 mg Total 120 mg

(1) to (6) were mixed in an ordinary manner, and tabletted into tabletsusing a tabletting machine.

EXPERIMENTAL EXAMPLE 1

The following procedures in this Example were carried out according tothe methods described in Molecular Cloning —Cold Spring HarborLaboratory (1989) or protocol specified by manufacturers.

(1) Cloning of Human Adenosine A₃ Receptor

Cloning of the human adenosine A₃ receptor gene was carried out by thepolymerase chain reaction (PCR) from human brain cDNA. Using 1 ng ofbrain cDNA (Quick-Clone cDNA, TOYOBO, Osaka) as template, PCR wasperformed in DNA Thermal Cycler 480 (Perkin Elmer) (reaction conditions:35 cycles of 1 min at 95° C., 1 min at 66° C., and 2 min at 75° C.) bymixing primers (50 pmol each),

5′-CGCCTCTAGACAAGATGCCCAACAACAGCACTGC-3′ [Sequence No. 1] and5′-CGGGGTCGACACTACTCAGAATTCTTCTCAATGC-3′ [Sequence No. 2], which weredesigned referring to nucleotide sequence of adenosine A₃ receptor genereported by Salvatore et. al., (Proc. Natl. Acad. Sci. U. S. A.,90:10365-10369, 1993) and TaKaRa LA PCR Kit Ver.2 (TaKaRa Shuzo Co.Ltd., Kyoto). The PCR product was electrophoresed and 1.0 kb DNAfragment was recovered. The DNA fragment encoding adenosine A₃ receptorwas cloned using Original TA Cloning Kit (FUNAKOSHI, Tokyo).

Thus obtained plasmid was digested with Xba I (TaKaRa Shuzo Co. Ltd.,Kyoto), blunted with T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto)and digested with Sal I (TaKaRa Shuzo Co. Ltd., Kyoto) to obtainadenosine A₃ receptor gene fragment.

(2) Construction of Human Adenosine A₃ Receptor Expression Plasmid

The SRα promoter from pTB1411 disclosed in JP 5-076385 A was ligatedinto the pCI vector (Promega, Tokyo), which was digested with Bgl II(TaKaRa Shuzo Co. Ltd., Kyoto), blunted and digested with EcoRI (TaKaRaShuzo Co. Ltd., Kyoto) subsequently. The resulting plasmid, designatedas pCI-SRα, was then digested with Cla I (TaKaRa Shuzo Co. Ltd., Kyoto)and blunted with T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto). Onthe other hand, pGFP-C1 (TOYOBO, Osaka) was digested with Bsu 36I(DAIICHIKAGAKUYAKUHIN, Tokyo) and the 1.63 kb fragment was recoveredafter the blunting with T4 DNA polymerase. Both were ligated to thepCI-SRα vector using DNA Ligation kit (TaKaRa Shuzo Co. Ltd., Kyoto).The ligation mixture was used to transform E. coli JM109 competent cells(TaKaRa Shuzo Co. Ltd., Kyoto). The resulting plasmid thus obtained wasdesignated as pMSRαneo.

pMSRαneo was digested with EcoRI (TaKaRa Shuzo Co. Ltd., Kyoto), bluntedwith T4 DNA polymerase (TaKaRa Shuzo Co. Ltd., Kyoto) and then digestedwith Sal I (TaKaRa Shuzo Co. Ltd., Kyoto) to obtain DNA at size of 5.4kb. This was ligated with adenosine A₃ receptor obtained in the above(1) by using DNA Ligation kit (TaKaRa Shuzo Co. Ltd., Kyoto). Theligation mixture was used to transform E. coli JM109 competent cells(TaKaRa Shuzo Co. Ltd., Kyoto). The plasmid thus obtained was designatedas pA3SRα.

(3) Transfection of Adenosine A₃ Receptor Expression Plasmid into CHO(dhfr⁻) and the Expression

CHO (dhfr⁻) cells were grown on Ham's F-12 medium (Nihon Seiyaku, Tokyo)supplement with 10% fetal bovine serum (Life Tech Oriental; LifeTechnologies, Inc., Rockville, Md., USA) in a 750 ml Tissue cultureflask (Becton Dickinson, Mt. View, Calif.). The growing cells weretreated with 0.5 g/L trypsin-0.2 g/L EDTA (Life Technologies, Inc.,Rockville, Md., USA) to harvest, washed with PBS (phosphate bufferedphysiological saline, Life Technologies, Inc., Rockville, Md., USA),centrifugated at 1000 rpm for 5 min, and suspended in PBS.

Transfection with DNA into the cells was performed by using a GenePulser (Bio-Rad) under the following conditions. Namely, 8×10⁶ cells andthe plasmid pA₃SRαfor expression of human adenosin A₃ receptor wereadded to a 0.4 cm gap cuvette and electroporation was performed in avolume of 0.8 mL at voltage of 0.25 kV, and capacitance of 960 μF. Thetransfected cells were transferred into Ham's F-12 medium containing 10%fetal bovine serum, cultivated for 24 hours, harvested, suspended inHam's F-12 media supplement with 10% fetal bovine serum and 500 μg/mlgeneticin (Life Technologies Inc., Rockville, Md., USA) at a celldensity of 10⁴ cells/mL. The cells were plated onto 96 well plates(Becton Dickinson) containing Ham's F-12 media supplement with 10% fetalbovine serum and 500 μg/mL geneticin (Life Technologies Inc., Rockville,Md., USA) at a cell density of 10⁴ cells/mL.

The geneticin resistant cells thus obtained were further cultivated on24 well plates (Becton Dickinson) and the cells expressing adenosine A₃receptor were selected from them as follows. The cells were incubated inassay buffer I (HBSS (Hanks' balanced salt solution, Wako chemicals,Osaka) containing 0.1% BSA (bovine serum albumin), 0.25 mM PMSF(phenylmethylsulfonyl fluoride), 1 μg/mL pepstatin, and 20 ug/mLleupeptin) to which was added 50 pM ¹²⁵I-AB-MECA(4-aminobenzyl-5′-N-methylcarboxamide adenosine, Amersham) as ligand,for 1 hour, and washed with assay buffer I. The radioactivity associatedwith the cell was measured in a y-counter to select A₃AR/CHO cells whichspecifically bind to the ligand.

(4) Cell Membrane Preparation of the Transfectant Expressing AdenosineA₃ Receptor

After A₃AR/CHO cells obtained in the above (3) were cultivated in Ham'sF-12 medium containing 10% fetal bovine serum for 2 days, the cells weretreated with PBS plus 0.02% EDTA, centrifuged to collect, resuspended inassay buffer II (50 mM Tris-HCl (pH7.5), 1 mM EDTA, 10 mM MgCl₂, 0.25 mMPMSF, 1 μg/mL pepstatin, and 20 μg/mL leupeptin) and homogenized usingPolytron homogenizer (PT-3000, KINEMATICA AG: 20,000 rpm, 20 sec, 3times). This suspension was centrifuged at 2,000 rpm for 10 min andsupernatant fraction containing cell membranes was obtained. Thesupernatant fraction was ultra-centrifuged at 30,000 rpm (model L8-70M,rotor 70Ti, Beckman) for 1 hour.

Thus obtained pellet was resuspended in assay buffer II containing 2unit/mL adenosine deaminase (Boehriger Mannheim) and incubated at 30° C.for 30 min. The suspension was ultra-centrifuged under the samecondition as above and the cell membrane fraction was obtained as thepellet.

(5) Binding Assays with Adenosine A₃ Receptor

10 rM of [³H]-NECA (Amersham Life Sciences, Inc., Tokyo) as ligand wasadded to the reaction mixture including test compound at variousconcentration and 100 μg/mL of membranes obtained in (4) in assay bufferII. The reaction mixture was incubated for 1 hour at room temperatureand filtrated through the Unifilter GF/C (Packard Instrument Company) totransfer the membrane onto the filter, using Cell Harvester (PackardInstrument Company). The filter was washed three times with ice-cold 50mM Tris-HCl (pH 7.5), and dried. Then, Microscint-0 was placed on thefilter and radioactivity retained on the filter was determined byTop-Count (Packard Instrument Company). The concentration that inhibits50% specific binding (IC₅₀) to the membrane of [³H]-NECA were calculatedby PRISM 2.01 (Graph Pad Software).

As a result, IC₅₀ value of Example Compound 1 was 3.5 nM. This resultshows that the compound (I) has a high affinity for adenosine A₃receptor.

INDUSTRIAL APPLICABILITY

Since compounds (I) and (Ia) have a excellent A₃ adenosine receptorantagonistic activity and are useful for preventing and/or treatingadenosine A₃ receptor relating diseases.

What is claimed is:
 1. A compound represented by the formula:

wherein: ring A is a benzene ring which may have 1 to 5 substituentsselected from the group consisting of (i) halogen atom, (ii) C₁₋₃alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C₁₋₆alkyl, (vi) optionally halogenated C₂₋₆ alkenyl, (vii) carboxy C₁₋₆alkyl, (viii) carboxy C₂₋₆ alkenyl, (ix) optionally halogenated C₂₋₆alkynyl, (x) optionally halogenated C₃₋₆ cycloalkyl, (xi) C₆₋₁₄ aryl,(xii) optionally halogenated C₁₋₆ alkoxy, (xiii) C₁₋₆alkoxy-carbonyl-C₁₋₆ alkoxy, (xiv) hydroxy, (xv) C₆₋₁₄ aryloxy, (xvi)C₇₋₁₆ aralkyloxy, (xvii) mercapto, (xviii) optionally halogenated C₁₋₆alkylthio, (xix) C₆₋₁₄ arylthio, (xx) C₇₋₁₆ aralkylthio, (xxi) amino,(xxii) mono-C₁₋₆ alkylamino, (xxiii) mono-C₆₋₁₄ arylamino, (xxiv)mono-C₇₋₁₆ aralkylamino, (xxv) di-C₇₋₁₆ aralkylamino, (xxvi) di-C₁₋₆alkylamino, (xxvii) di-C₆₋₁₄ arylamino, (xxviii) formyl, (xxix) carboxy,(xxx) C₁₋₆ alkyl-carbonyl, (xxxi) C₃₋₆ cycloalkyl-carbonyl, (xxxii) C₁₋₆alkoxy-carbonyl, (xxxiii) C₆₋₁₄ aryl-carbonyl, (xxxiv) C₇₋₁₆aralkyl-carbonyl, (xxxv) C₆₋₁₄ aryloxy-carbonyl, (xxxvi) C₇₋₁₆aralkyloxy-carbonyl, (xxxvii) 5- or 6-membered heterocyclic-carbonylselected from the group consisting of nicotinoyl, isonicotinoyl,thienoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl,piperazin-1-ylcarbonyl and pyrrolidin-1-ylcarbonyl, (xxxviii) carbamoyl,(xxxix) thiocarbamoyl, (xxxx) mono-C₁₋₆ alkyl-carbamoyl, (xxxxi) di-C₁₋₆alkyl-carbamoyl, (xxxxii) C₆₋₁₄ aryl-carbamoyl, (xxxxiii) 5- or6-membered heterocylic carbamoyl selected from the group consisting of2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl,2-thienylcarbamoyl and 3-thienylcarbamoyl, (xxxxiv) C₁₋₆ alkylsulfonyl,(xxxxv) C₆₋₁₄ arylsulfonyl, (xxxxvi) formylamino, (xxxxvii) C₁₋₆alkyl-carbonylamino, (xxxxviii) C₆₋₁₄ aryl-carbonylamino, (xxxxix) C₁₋₆alkoxy-carbonylamino, (xxxxx) C₁₋₆ alkylsulfonylamino, (xxxxxi) C₆₋₁₄arylsulfonylamino, (xxxxxii) C₁₋₆ alkyl-carbonyloxy, (xxxxxiii) C₆₋₁₄aryl-carbonyloxy, (xxxxxiv) C₁₋₆ alkoxy-carbonyloxy, (xxxxxv) mono-C₁₋₆alkyl-carbamoyloxy, (xxxxxvi) di-C₁₋₆ alkyl-carbamoyloxy, (xxxxxvii)C₆₋₁₄ aryl-carbamoyloxy, (xxxxxviii) nicotinoyloxy, (xxxxxix) 5- to7-membered saturated cyclic amino which may be substituted by asubstituent selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₄aryl, C₁₋₆ alkyl-carbonyl, oxo, and 5- to 10-membered aromaticheterocylic group selected from 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,1-indolyl, 2-indolyl, 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl,3-benzo[b]thienyl, 2-benzo[b]furanyl, or 3-benzo[b]furanyl, (xxxxxx) 5-to 10-membered aromatic heterocylic group selected from 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl,4-isoquinolyl, 5-isoquinolyl, 1-indolyl, 2-indolyl, 3-indolyl,2-benzothiazolyl, 2-benzo[b]thienyl, 3-benzo[b]thienyl,2-benzo[b]furanyl, or 3-benzo[b]furanyl, and (xxxxxxi) sulfo; ring B mayhave 1 or 2 substituents selected from the same substituents as definedfor ring A; and R¹ is C₃₋₆ cycloalkyl group, C₆₋₁₄ aryl group or amonovalent group formed by removing any one hydrogen atom from a 5- to14-membered heterocyclic ring selected from the group consisting of (i)5- to 14-membered aromatic heterocyclic ring selected from the groupconsisting of thiophene, benzo[b]thiophene, benzo[b]furan,benzimidazole, benzoxazole, benzothiazole, benzisothiazole,naphtho[2,3-b]thiophene, furan, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole,purine, 4H-quinolizine, isoquinoline, quinoline, phthalazine,naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole,β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole,phenothiazine, isoxazole, furazan and phenoxazine, and a ring formed byfusion of the 5- to 14-membered aromatic heterocyclic ring with one ortwo benzene rings, (ii) 5- to 10-membered aliphatic heterocyclic ringselected from the group consisting of pyrrolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, morpholine,thiomorpholine, dioxazole, oxadiazoline, thiadiazoline, triazoline,thiadiazole and dithiazole, and (iii) 7- to 10-membered bridgedheterocyclic ring selected from the group consisting of quinuclidine and7-azabicyclo[2.2.1]heptane; each of which may have 1 to 5-substitutentsselected from the same substituents as defined for ring A; or a saltthereof.
 2. The compound according to claim 1, wherein R¹ is themonovalent group formed by removing any one hydrogen atom from the 5- to14-membered heterocyclic ring.
 3. The compound according to claim 1,wherein the monovalent group formed by removing any one hydrogen atomfrom the 5- to 14-membered heterocyclic ring is a 5- to 14-memberednitrogen-containing aromatic heterocyclic group.
 4. The compoundaccording to claim 1, wherein the monovalent group formed by removingany one hydrogen atom from the 5- to 14-membered heterocyclic ring is a2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-quinolyl group,3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 8-quinolyl group,1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group,5-isoquinolyl group, pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinylgroup, 3-pyrrolyl group, 2-imidazolyl group, 3-pyridazinyl group,3-isothiazolyl group, 3-isoxazolyl group, 1-indolyl group, 2-indolylgroup, 3-indolyl group or 2-benzothiazolyl group.
 5. The compoundaccording to claim 1, wherein the monovalent group formed by removingany one hydrogen atom from the 5- to 14-membered heterocyclic ring is a5- or 6-membered nitrogen-containing aromatic heterocyclic group.
 6. Thecompound according to claim 1, wherein the monovalent group formed byremoving any one hydrogen atom from the 5- to 14-membered heterocyclicring is a 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, pyrazinylgroup, 2-pyrimidinyl group, 4-pyrimidinyl group, 3-pyrrolyl group,3-pyridazinyl group, 3-isothiazolyl group or 3-isoxazolyl group.
 7. Thecompound according to claim 1, wherein the monovalent group formed byremoving any one hydrogen atom from the 5- to 14-membered heterocyclicring is a pyridyl group.
 8. The compound according to claim 1, whereinR¹ is a 4-pyridyl group.
 9. The compound according to claim 1, whereinR¹ is an optionally substituted nitrogen-containing aromaticheterocyclic group.
 10. The compound according to claim 1, wherein ringA is a benzene ring which may be substituted with C₁₋₆ alkoxy, or one ortwo C₁₋₆ alkyls.
 11. The compound according to claim 1, wherein ring Ais a benzene ring which may be substituted with C₁₋₆ alkoxy.
 12. Thecompound according to claim 1, wherein the substituent of ring B isamino.
 13. The compound according to claim 1, wherein ring A is abenzene ring which may be substituted with C₁₋₆ alkoxy, or one or twoC₁₋₆ alkyls, ring B may be substituted with amino, and R¹ is a pyridylgroup.
 14. The compound according to claim 1, wherein ring A is abenzene ring which may be substituted with C₁₋₆ alkoxy, ring B may besubstituted with amino, and R¹ is a pyridyl group.
 15. The compoundaccording to claim 1 which is represented by the formula:

wherein R² and R³ are the same or different, and are hydrogen atom or asubstituent selected from the same substitutents as defined for ring Ain claim 1, and ring A and R¹ are as defined in claim 1, or a saltthereof.
 16. The compound according to claim 15, wherein R³ is hydrogenatom.
 17. (1)5-amino-3-(4-methoxyphenyl)-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor its salt, (2)5-amino-3-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)-7H-thiazolo[3,2-a]pyrimidin-7-oneor its salt, or (3)5-amino-3-(3,5-dimethylphenyl)-2-(4-pyridyl)-7H-thiazolo(3,2-a]pyrimidin-7-oneor its salt.
 18. A prodrug of the compound according to claim 1, whichis a hydrolyzable derivative of the compound according to claim
 1. 19. Aprocess for producing the compound according to claim 1 or a saltthereof, which comprises reacting a compound represented by the formula:

wherein ring A and R¹ are as defined in claim 1, or its salt, with acompound represented by the formula: R²—C≡C—COOH wherein R² is hydrogenor a substituent of ring B as defined in claim 1, or its salt orreactive derivative, or a compound represented by the formula:NCCHR³COOH wherein R³ is hydrogen or a substituent of ring B as definedin claim 1, or its salt or reactive derivative.
 20. A pharmaceuticalcomposition comprising a compound according to claim 1, or a saltthereof, together with a pharmaceutically acceptable carrier.
 21. Apharmaceutical composition, which comprises a prodrug according to claim18, or a salt thereof, together with a pharmaceutically acceptablecarrier.
 22. The prodrug according to claim 18, wherein the hydrolyzablederivative is an acylate, alkylate, amide, ester, phosphorylate orborate of the compound according to claim
 1. 23. A method for treatingasthma, which comprises administering to a mammal an effective amount ofthe compound according to claim 1, or a salt thereof, or a prodrugthereof which comprises a hydrolyzable derivative thereof.